Viral complementation of immunodeficiency confers protection against enteric pathogens via interferon-λ

Abstract

Commensal microbes profoundly impact host immunity to enteric viral infections1. We have shown that the bacterial microbiota and host antiviral cytokine interferon-λ (IFN-λ) determine the persistence of murine norovirus in the gut2,3. However, the effects of the virome in modulating enteric infections remain unexplored. Here, we report that murine astrovirus can complement primary immunodeficiency to protect against murine norovirus and rotavirus infections. Protection against infection was horizontally transferable between immunocompromised mouse strains by co-housing and fecal transplantation. Furthermore, protection against enteric pathogens corresponded with the presence of a specific strain of murine astrovirus in the gut, and this complementation of immunodeficiency required IFN-λ signalling in gut epithelial cells. Our study demonstrates that elements of the virome can protect against enteric pathogens in an immunodeficient host.

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Fig. 1: Specific immunodeficient mouse strains are protected against murine norovirus and rotavirus infection.
Fig. 2: Antiviral protection is transmissible to immunodeficient, but not immunocompetent, mice.
Fig. 3: Murine astrovirus STL5 confers protection against murine norovirus infection.
Fig. 4: Intestinal IFN-λ signalling is essential for protection against MNoV in immunocompromised mice.

Code availability

The code used for constructing the phylogenetic tree is available at GitHub (https://github.com/RachelRodgers/STL5-phylogenetics).

Data availability

The data from this study are available in the main paper and Supplementary Information. Sequencing data have been uploaded to the European Nucleotide Archive with accession number PRJEB31115.

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Acknowledgements

We acknowledge all members of the Baldridge laboratory for helpful discussions. We also thank J. Hoisington-Lopez for assistance with sequencing, D. Kreamalmeyer for animal care and breeding, the Washington University Pulmonary Morphology core facility for assistance with histology, and J. White and the Washington University Central Gnotobiotic Facility for assistance with germ-free mice. We are grateful to the Estes laboratory for providing murine rotavirus. H.I. was supported by the Children’s Discovery Institute of Washington University and a St Louis Children’s Hospital Postdoctoral Research grant (MI-F-2018-712). S.L. was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2016R1A6A3A03012352). A.O. was funded by the Pediatric Infectious Diseases Society/St Jude Children’s Research Hospital Fellowship Program in Basic Research and NIH training grant T32AI106688. C.C.Y. was supported by NIH training grant T32AI007163. S.S.-C. was supported by ALSAC and NIH grant R03 AI126101-01. J.J.M. was supported by NIH grant K08 AR07091. M.T.B. was supported by NIH grants K22 AI127846, R01 AI127552, R01 AI139314 and R01 AI141478, Digestive Diseases Research Core Centers P30 DK052574, the Pew Biomedical Scholars Program and the Global Probiotics Council’s Young Investigator Grant for Probiotics Research.

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H.I., S.L., T.A., M.S., S.T.P., M.L., T.-C.L., C.C.Y. and M.T.B. performed the experiments. H.I., S.L., T.A., A.O., G.Z., M.S., S.T.P., M.L., T.C.L., C.C.Y., B.S., R.R., S.S.-C., J.J.M. and M.T.B analysed the results. H.I., S.L., S.S.-C., J.J.M and M.T.B designed the project. H.I., S.L. and M.T.B. wrote the manuscript. All authors read and edited the manuscript. All reagents are available from M.T.B. under a material transfer agreement with Washington University.

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Correspondence to Megan T. Baldridge.

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C.C.Y. and G.Z. hold a patent for detection of murine astrovirus. The authors declare no additional conflicts of interest.

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Ingle, H., Lee, S., Ai, T. et al. Viral complementation of immunodeficiency confers protection against enteric pathogens via interferon-λ. Nat Microbiol 4, 1120–1128 (2019). https://doi.org/10.1038/s41564-019-0416-7

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